Empagliflozin Improves Mitochondrial Biogenesis and Ameliorates Experimental Pulmonary Vascular Remodeling, But May Not Benefit Patients with Pulmonary Arterial Hypertension

BackgroundThe sodium glucose cotransporter 2 (SGLT2) inhibitor may improve mitochondrial biogenesis and attenuate pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). We investigated the impact of empagliflozin in PAH. MethodsLung sections and primary cell cultures isolated from microvascular endothelial cells (MVECs) were collected from control subjects and PAH patients. MVECs were treated with empagliflozin and mitochondrial biogenesis, cell metabolism, oxidative stress and cell proliferation were evaluated. Subsequently, PAH was induced in male and female rats (n=12 respectively) with SU5416 injection (25 mg/kg s.c.) followed by 3 weeks of hypoxia (10% O2), the experimental PAH model known to mimic human PAH pathophysiology. Four weeks after SU5416 injection, rats were treated by empagliflozin (300 mg/kg chow, n=12) or placebo (n=12) for 4 weeks and hemodynamic, protein and histological analyses were performed. In addition, we conducted a phase IIa proof of concept trial, EMPHOWER, to assess the feasibility of 12 weeks of empagliflozin treatment in PAH patients. ResultsImmunofluorescent staining of human lung tissue showed expression of SGLT2 in the intima of small pulmonary arteries from PAH patients, not controls. In comparison to control MVECs, PAH MVECs showed increased protein expression of SGLT2, along with decreased expression of the peroxisome proliferator-activated receptor gamma coactivator-1. Furthermore, empagliflozin enhanced expression of mitochondrial encoded genes and mitochondrial respiration, suggesting increased mitochondrial biogenesis. Moreover, empagliflozin significantly attenuated oxidative stress and proliferation of PAH MVECs. In SuHx rats, chronic treatment with empagliflozin significantly reduced pulmonary vascular resistance and thickening of the intima of small pulmonary arteries. Finally, 8 patients diagnosed with idiopathic and heritable PAH were enrolled in the phase IIa EMPHOWER trial. There was no discontinuation of empagliflozin during the study period and there were no treatment associated serious adverse events. There were no changes in biomarkers, WHO functional class, six-minute walk distance, or EMPHASIS score. However, RV ejection fraction and RV global longitudinal strain slightly worsened after empagliflozin treatment (from 45 {+/-} 10% to 38 {+/-} 12%, P=0.036, and from -15.2 {+/-} 4.2% to -13.2 {+/-} 3.96%, P=0.002, respectively). ConclusionSGLT2 expression is increased in the PAH endothelium. Treatment with empagliflozin improves mitochondrial biogenesis and attenuates proliferation of PAH MVECs. Empagliflozin attenuates pulmonary vascular remodeling in experimental PAH. While twelve weeks of empagliflozin treatment seemed feasible in patients with idiopathic or hereditary PAH, we observed signs of RV deterioration. Clinical perspectiveWhat is new? O_LIThis is the first study to demonstrate the role of sodium glucose cotransporter 2 (SGLT2) in the endothelial cell proliferation of pulmonary arterial hypertension (PAH). C_LIO_LISGLT2 was expressed and increased in microvascular endothelial cells (MVECs) from the lung of PAH patients accompanied by suppression of peroxisome proliferator-activated receptor gamma coactivator-1. C_LIO_LIEmpagliflozin improved mitochondrial biogenesis and respiration in PAH MVECs. C_LIO_LIEmpagliflozin reversed pulmonary angioproliferation and attenuated pulmonary vascular resistance in experimental PAH rats. C_LIO_LIThe EMPHOWER PoC study showed the feasibility of 12 weeks of empagliflozin treatment in PAH, however, right ventricular function assessed by cardiac magnetic resonance imaging worsened. C_LI What are the clinical implications O_LISGLT2 inhibition may improve mitochondrial respiration and reverse pulmonary vascular remodeling in PAH. C_LIO_LIThe effect of empagliflozin on right ventricular function requires further caution and investigation. C_LI